Among gliomas, the most common primary brain tumor in adults, glioblastoma multiforme (GBM) is the most malignant. Despite advances in surgery, chemotherapy, and radiation, GBM remains a devastating disease. A hallmark of GBM is ts ability to infiltrate white matter tracts, but little is known about the molecular mechanisms underlying the acquisition of nvasive characteristics. PTEN, which encodes a negative regulator of the phosphoinositide-3 kinase pathway, is commonly mutated in GBMs and has been implicated in regulation of tumor migration. The underlying hypothesis of this proposal is that abnormalities in processes that determine normal glial development contribute to malignant transformation. Previous studies have identified a critical role for activation of STAT3, a transcription factor, in the differentiation of neural stem cells into astrocytes. In preliminary data, STAT3 loss increased the migration of murine astrocytes in vitro. Moreover, in human GBM samples, low PTEN expression correlated with low STAT3 activity. Together, these results raise the intriguing possibility that STAT3 inhibits invasiveness in PTEN-deficient GBMs. The specific aims of this study are: 1) to test the role of STAT3 in GBM invasiveness in brain slice assay and in vivo, 2) to dentify STAT3-responsive genes that control GBM migration using expression array analysis, and 3) to identify novel cell-intrinsic mechanisms that regulate GBM invasiveness through an RNA interference-based screen. These aims will be pursued using a combination of molecular biology, cell culture, brain slice preparation, and in vivo approaches. Completion of these aims will elucidate the role of STAT3 in GBM invasiveness and potentially reveal new therapeutic argets against GBM. [unreadable] [unreadable] [unreadable] [unreadable]